title: Phosphorylated insulin-like growth factor-1 receptor (pIGF1R) is a poor prognostic factor in brain metastases from lung adenocarcinomas.
abstract: A greater understanding of brain metastases is imperative for developing novel therapeutic strategies. Our previous study showed that insulin-like growth factor (IGF) signaling pathway was activated in brain-tropic cancer cells. In this study, we investigated the clinical relevance of activated (phosphorylated) IGF-1 receptor (pIGF1R) expression in brain metastases originating from lung adenocarcinomas. All pathologically confirmed brain metastases from lung adenocarcinomas, with available archived specimens from January 1998 to December 2009 at National Taiwan University Hospital, were assessed immunohistochemically for pIGF1R expression using H-score criteria. A median H-score was used as a cutoff point to define high or low pIGF1R expression. The mutation status in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) was examined using direct sequencing. The prognostic significance of pIGF1R expression, its correlations with clinicopathological characteristics, and EGFR status were evaluated. In the 86 cases, high membranous/cytoplasmic pIGF1R expression in brain metastases correlated with a shorter median survival (10.8 vs 27.8 mo, P = 0.003). This correlation was more significant in patients with EGFR mutations [hazard ratio (HR) 2.38, 95 % confidence interval (CI) 1.19-4.77 for EGFR mutations; HR 1.99, 95 % CI 0.95-4.15 for EGFR wild type] and remained statistically significant in multivariate analysis after adjusting for the effects of other potential prognostic factors, including the graded prognostic assessment score, solitary brain metastasis, extracranial metastatic status, EGFR mutations, and treatment using EGFR tyrosine kinase inhibitors. Although we also identified nuclear pIGF1R expression, this result was prognostically non-significant. Our study results showed that high membranous/cytoplasmic pIGF1R expression in brain metastases was a poor prognostic factor, more significantly in patients with EGFR mutations than in those with wild-type EGFRs.
authors.affiliation: National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, No. 7, Chung-Shan South Rd, Taipei, 100, Taiwan.
authors.forename: Pei-Fang
authors.initials: PF
authors.lastname: Wu
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Huang
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.forename: Yen-Shen
authors.initials: YS
authors.lastname: Lu
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Shih
authors.forename: Shang-Gin
authors.initials: SG
authors.lastname: Wu
authors.forename: Ching-Hung
authors.initials: CH
authors.lastname: Lin
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000556:secondary; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism / Q000556:secondary*; D018196:Carcinoma, Adenosquamous / Q000378:metabolism / Q000556:secondary; D018287:Carcinoma, Large Cell / Q000378:metabolism / Q000556:secondary; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1